According to professionals, medication nonadherence is often attributed to adverse effects or early remission. There is, however, little evidence to support these attributions. Our aim was to study the predictors of nonadherence in primary care patients with a new antidepressant (AD) prescription. We used a prospective cohort study with 6-month follow-up among 147 primary care patients who were newly prescribed with a nontricyclic AD for depression. They were recruited in 19 community pharmacies in the Netherlands that were linked to 85 general practitioners. An electronic pill container (medication event monitoring system; Aardex Ltd, Untermüli, Switzerland) registered the adherence for 6 months. The predictive values of patient, prescriber, pharmacist, and drug-related characteristics were expressed in univariate and multivariate odds ratios with 95% confidence intervals. Outcome measures showed nonadherence, as expressed in these factors (all dichotomous): (1) incorrect intakes (<80% period coverage); (2) extra pill intakes (>1 per day); (3) drug holidays (>or=1). We found that not only a positive drug attitude, the most important predictor, but also adverse effects, early treatment response, longer onset of depression, and a higher educational level predicted the correct intake of ADs. Extra intakes were predicted by ADs with a shorter half-life and by experience of adverse effects. Drug holidays were predicted by patients with less social support and a negative drug attitude. In conclusion, the predictors of adherence were multifactorial and varied across the 3 adherence types. A positive drug attitude emerged as the most important predictor for correct intakes and drug holidays.